PARP inhibitors (PARPi) have demonstrated efficacy in tumors with germline breast cancer susceptibility genes (gBRCA) 1 and 2 mutations, but further factors influencing response to PARPi are poorly ...understood.
Breast cancer tumor tissue from patients with gBRCA1/2 mutations from the phase III EMBRACA trial of the PARPi talazoparib versus chemotherapy was sequenced using FoundationOne CDx.
In the evaluable intent-to-treat population, 96.1% (296/308) had ≥1 tumor BRCA (tBRCA) mutation and there was strong concordance (95.3%) between tBRCA and gBRCA mutational status. Genetic/genomic characteristics including BRCA loss of heterozygosity (LOH; identified in 82.6% of evaluable patients), DNA damage response (DDR) gene mutational burden, and tumor homologous recombination deficiency assessed by genomic LOH (gLOH) demonstrated no association with talazoparib efficacy.
Overall, BRCA LOH status, DDR gene mutational burden, and gLOH were not associated with talazoparib efficacy; however, these conclusions are qualified by population heterogeneity and low patient numbers in some subgroups. Further investigation in larger patient populations is warranted.
TPS623
Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX have ...identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for in-breast recurrence and breast preservation in women intending endocrine therapy (ET) for stage 1 invasive breast cancer (ER &/or PR positive, HER2-negative with an Oncotype DX Recurrence Score RS of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (<11, 11-18). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER &/or PR positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS of ≤18 (diagnostic core biopsy or resected specimen). Primary endpoint is in-breast recurrence (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% vs 91.6% for the omission of RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1% per yr. Some of the T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. Current accrual (02-08-2023) is 370 screened and 323 randomized (~87% of predicted accrual). Clinical trial information: NCT04852887 .
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12115
Background: FCR affects 50-70% of cancer survivors. There are no validated oncologist-delivered FCR interventions. This multicentre, single-arm study sought to determine the ...helpfulness, feasibility and efficacy of an oncologist-delivered FCR intervention. Methods: Women were invited to participate if they had completed local treatment, chemotherapy and/or HER2 targeted therapy for early stage breast cancer and had a FCR score >0 on the 42-item FCR Inventory. The brief intervention, delivered by their medical oncologist at routine follow-up, entailed 1) FCR normalisation; 2) provision of personalised prognostic information; 3) take-home education sheet on recurrence symptoms; and 4) advice on managing worry. Consultations were audio-recorded. FCR, need for help, depression and anxiety were assessed before the intervention (T0), and at one week (T1) and three months (T2) after the intervention. Satisfaction with the intervention was assessed at T1. The primary outcome was participant-rated helpfulness. Secondary outcomes included feasibility (response rate, time taken for intervention) and efficacy. Results: Five oncologists delivered the intervention to 61 women (255 women invited; response rate 24%). The mean age was 57 ± 13 years. The mean time since breast cancer diagnosis was 2.5 ± 1.3 years. Forty-three (72%) were on adjuvant hormonal therapy. Overall, 58 women (95%) found the intervention helpful and 59 (98%) would recommend it to others. FCR severity, and the proportion of women with clinically significant FCR decreased significantly over time. There were no significant changes in unmet need, depression, or anxiety. Forty (66%) of consultations were recorded. Mean consultation length was 22 minutes (range 12-37 minutes) and mean intervention length was 9 minutes (3-20 minutes). The intervention was perceived as useful and feasible by oncologists, all of whom have used components of the intervention to help manage FCR in other breast cancer patients. Conclusions: A brief oncologist-delivered intervention to address FCR is helpful and feasible, and has shown preliminary efficacy in reducing FCR. Plans for an implementation study amongst oncologists in Australia are underway. Clinical trial information: ACTRN12618001615279 . Table: see text
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1029
Background: In the EMBRACA trial (NCT01945775), the poly(ADP-ribose) polymerase inhibitor (PARPi) TALA significantly improved progression-free survival (PFS) versus PCT in patients ...(pts) with germline BRCA1/2-mutated HER2-negative locally advanced/metastatic breast cancer (BC) (8.6 vs 5.6 months mo; hazard ratio HR, 95% CI 0.54 0.41-0.71; P < 0.0001). Predictive markers for response to PARPi, other than germline BRCA1/2 mutational status, are largely unknown. A previous analysis investigated biomarkers associated with long and short responders in EMBRACA. Here, we report the clinical characteristics of long and short responders. Methods: Pts were randomized 2:1 to TALA or PCT. In this retrospective analysis, pts in the intent-to-treat (ITT) population were mapped into two groups based on response: LONG (pts in TALA arm with overall survival OS ≥30 mo and duration of treatment ≥24 mo; pts in PCT arm with OS ≥30 mo); SHORT (pts in either arm with a PFS event progressive disease by Independent Radiological Facility or death ≤12 wks). Data cutoff date was Sept 30, 2019. Results: Of 431 pts randomized, 412 pts were treated (286 received TALA; 126 received PCT). In the ITT population, 37 pts receiving TALA and 34 pts receiving PCT were identified as LONG responders; 40 pts receiving TALA and 32 pts receiving PCT were SHORT responders. The Table shows a summary of pt characteristics for LONG and SHORT responders. More pts with HR+ BC and no prior CT for ABC were associated with LONG response; more pts with TNBC and ≥2 prior CT regimens or platinum were associated with SHORT response (Table). Median treatment duration for LONG responders (n = 37, TALA; n = 31, PCT) was 33.5 (24.0-61.4) mo for TALA and 7.6 (1.1-36.3) mo for PCT; 51.4% receiving TALA and 91.2% receiving PCT had subsequent therapy. In SHORT responders, median treatment duration was 2.0 (0.1-5.5) mo (TALA) and 1.4 (0.2-5.6) mo (PCT); 67.5% and 68.8% received subsequent therapy following TALA or PCT, respectively. Conclusions: In this clinical characterization of responders from the EMBRACA study, a higher number of LONG responders had HR+ BC and received no prior CT for ABC. A greater proportion of SHORT responders had TNBC and received ≥2 prior CT regimens or platinum. Further investigation is warranted in a larger number of pts. Clinical trial information: NCT01945775 .Table: see text
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1090
Background: In the EMBRACA trial (NCT01945775) of pts with germline BRCA1/2-mutated HER2-negative locally advanced/metastatic breast cancer (ABC), the poly(ADP-ribose) polymerase ...(PARP) inhibitor TALA significantly improved progression-free survival (PFS) vs PCT (8.6 vs 5.6 mo; HR 95% CI 0.54 0.41-0.71; P < 0.0001). Patient-reported outcomes favored TALA, and most common adverse events included anemia, fatigue, and nausea. Previous subgroup analyses found that pts with a history of CNS metastases had improved PFS for TALA vs PCT (HR 95% CI 0.32 0.15-0.68; P = 0.0016) and improved objective response rate (ORR) 63.2% vs 15.8%, respectively (odds ratio 95% CI 8.95 1.86-52.26; P = 0.0013). This retrospective subgroup analysis further explored the clinical characteristics and outcomes in pts with a history of CNS metastases in EMBRACA. Methods: Pts were randomized 2:1 to TALA or PCT. Pts with adequately treated and stable CNS metastases not requiring corticosteroids were included. This analysis assessed intracranial ORR and best overall response (BOR) based on investigator assessment per RECIST 1.1 in pts with intracranial disease at baseline (data cutoff 15-Sep-17), and overall survival (OS; data cutoff 30-Sep-19). Results: In the intent-to-treat (ITT) population, 63 pts (43/287 15.0% TALA and 20/144 13.9% PCT) had a history of CNS metastases, of which 33 (11.5%) pts (TALA) and 15 (10.4%) pts (PCT) had intracranial disease at baseline. Additional baseline characteristics are shown in the table. Intracranial ORR in pts with intracranial disease at baseline and unconfirmed complete or partial response was 18.2% (TALA) vs 20.0% (PCT) (odds ratio 95% CI 0.78 0.13-5.80; P = 0.765). In pts with intracranial disease at baseline, an intracranial BOR of stable disease was 69.7% for TALA vs 33.3% for PCT. Median OS in pts with a history of CNS metastases was 12.9 mo (95% CI 9.4-15.6) for TALA and 13.4 mo (95% CI 8.8-17.6) for PCT (HR 95% CI 0.67 0.37-1.2; P = 0.1936 stratified log-rank test). In the safety population (n = 43, TALA; n = 19, PCT), median treatment duration (range) with TALA was 5.0 (0.1-36.0) mo compared with 2.1 (0.4-6.9) mo for PCT. Conclusions: In this subgroup analysis, baseline characteristics between pts with a history of CNS metastases treated with TALA or PCT were comparable. More pts with intracranial disease at baseline treated with TALA vs PCT experienced stable disease. Intracranial ORR in pts with intracranial disease was 18.2% for TALA vs 20.0% for PCT. Treatment options for pts with a history of CNS metastases are limited and further investigation in larger data sets is warranted. Clinical trial information: NCT01945775 .Table: see text
Continuing medical education (CME) is challenging and often has limited impact on clinician behavior or patient outcomes. This study examined the impact of an online Qstream education program on ...senior clinicians to determine its utility for increasing clinician knowledge about the latest guidelines regarding genetic assessment and consideration of genetic testing for women with particular types of ovarian, fallopian tube and primary peritoneal cancer. Participants were recruited into a pilot study that involved responding to case-based scenarios at spaced and repeated intervals. At the completion of the program, semi-structured interviews were conducted to ascertain the impact on their knowledge and referral behavior. Findings from interviews were subject to thematic analysis that involved the identification of categories and themes. Twenty-one participants commenced the program, seventeen completed and twelve participated in semi-structured interviews. Thematic analysis yielded several themes including knowledge change, curriculum and format and changes in referral patterns. A majority of participants (
n
= 10) agreed the program had helped update their knowledge about referring women, and eight agreed they would now change their referral patterns. The use of QStream as an approach to CME has significant advantages when working with busy clinicians. QStream has a well accepted format and most participants indicated it is very appropriate for disseminating updates to clinical guidelines and protocols. It is important to supplement CME programs with other implementation techniques, such as audit and feedback as multifaceted approaches are more likely to result in behavior change.
Abstract
In early triple-negative breast cancer (eTNBC), platinum-based chemotherapy has been shown to improve pathological complete response, but recommendations to include platinum chemotherapy are ...not consistent in international guidelines. We performed a systematic review of published randomized control trials to assess to assess survival outcomes and quality of life for people with early TNBC. The results presented in this abstract have not yet been peer-reviewed by Cochrane. If the final version of the review meets the necessary standards, the review is expected to be published in the Cochrane Database of Systematic Reviews. Methods: Randomized controlled trials examining neoadjuvant or adjuvant platinum chemotherapy for eTNBC were included. We searched for published and unpublished data using standard Cochrane search strategies. The primary outcomes assessed were disease free survival (DFS) and overall survival (OS). Secondary outcomes included rate of pathological complete response (pCR), dose intensity and completion of regimens, grade III or IV toxicity related to chemotherapy, and quality of life. Prespecified subgroups included BRCA mutation status, HRD status, lymph node status, frequency of chemotherapy, type of platinum agent used, and the presence or absence of anthracycline chemotherapy. Results: From 3972 records, 19 published studies were eligible. Twenty six ongoing studies were identified. Risk of bias was judged low for most trials. There were 14 neoadjuvant chemotherapy trials, 4 adjuvant chemotherapy trials, and one trial of neoadjuvant and adjuvant therapy. Most trials used carboplatin (16 trials) followed by cisplatin (2), and lobaplatin (1). Eight trials had an anthracycline free intervention arm, 5 of which had a carboplatin-taxane intervention compared to an anthracycline-taxane control. All studies reporting DFS and OS used carboplatin. Twelve of 19 studies with a total of 3347 participants reported DFS data. Inclusion of platinum chemotherapy improved DFS in neoadjuvant and adjuvant setting (HR 0.63, 95% confidence interval (CI) 0.53-0.75; HR 0.69, 95% CI 0.54-0.88 respectively)). Eleven studies collected OS data, with a total of 3229 participants and 460 deaths reported. Inclusion of platinum chemotherapy in the regimen improved OS (neoadjuvant: HR 0.69, 95% CI 0.69, 0.55-0.86; adjuvant: 0.70, 95% CI 0.50 to 0.96). Median follow up for survival outcomes ranged from 36 – 97.6 months. Our analysis confirmed platinum chemotherapy increased pCR rates (RR 1.46 1.33-1.61, p< 0.00001). Subgroup analysis revealed that survival outcome benefits were seen regardless of BRCA mutation status, HRD status, lymph node status, or whether the intervention arm contained anthracycline chemotherapy or not. Platinum chemotherapy was associated with reduced dose intensity, with participants more likely to require chemotherapy delays (RR 2.23 1.70-2.94, 4 studies), dose reductions (RR 1.77 1.56-2.02, 6 studies) and early cessation of treatment (RR 1.20 1.04-1.38, 16 studies). Increased hematological toxicity occurred in the platinum group who were more likely to experience grade III/IV neutropenia (RR 1.55 1.45-1.66), anemia (RR 10.12 6.61-15.50) and thrombocytopenia (RR 7.59 5.10-11.29). There was no increase in febrile neutropenia (RR 1.16 0.89-1.49). Treatment-related death was very rare (7 events in 3094 patients) and similar across treatment groups (RR 0.58 0.14-2.33). Five studies collected quality of life data but did not report it. Conclusion: Platinum-based chemotherapy using carboplatin in the adjuvant or neoadjuvant setting improves long-term outcomes in eTNBC, regardless of the examined subgroups. This was at the cost of more frequent chemotherapy delays and dose reductions, and greater haematological toxicity. Benefit from platinum was seen both when platinum agents were added to anthracycline containing regimens, as well as in anthracycline-free regimens.
Citation Format: Sofia Mason, Melina Willson, Annabel Goodwin, Jane Beith, Sam J. Egger, Rachel F. Dear. Platinum-based chemotherapy for early triple-negative breast cancer: A Cochrane systematic review and meta-analysis abstract. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-06-01.
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1521
Background: In order to identify the ∼12% with inherited cancer predisposition, it is recommended that all men with metastatic prostate cancer (mPC) be offered testing. This has ...implications for treatment choices and cancer prevention in family. Limited geneticists/genetic counsellors globally present a major barrier to testing. We tested a potential solution, mainstreaming, where testing is performed by the patient’s oncologist. Methods: Men with mPC at three Australian sites were offered germline genetic testing at their medical oncology appointment. Panel testing ( ATM, BRCA1, BRCA2, BRIP1, CHEK2, EPCAM, FANCA, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51D and TP53) was performed on saliva/blood (Invitae). Primary outcomes were clinician and patient acceptability (modified Royal Marsden Satisfaction Questionnaires). Secondary outcomes included mutation rates and cost-effectiveness. A sample size of 44 provided 90% power, with a one-sided alpha of 5%, to distinguish a proportion of men happy with mainstreaming of 80% vs. 60% or less. Allowing for 25% drop-out, we aimed to recruit 60 men. Results: Of 66 men offered testing from April to November 2019, 63 (95%) accepted. Four pathogenic variants were identified (2 BRCA2, 1 NBN, 1 MSH6). 48 patients and eight clinicians completed questionnaires. Acceptability was high. All (48/48) patients were happy to have been tested, and 45/48 (94%) were happy to have been tested at their oncology appointment. All were happy to receive their results from their oncologist. All clinicians were satisfied mainstreaming and 88% (7/8) felt confident doing so. Mainstreaming was cost-effective, requiring 87% fewer genetic consultations than traditional genetic counselling. Conclusions: This study shows that mainstreaming of men with mPC is feasible, resource efficient and acceptable to both clinicians and patients. Widespread implementation as a new standard of care would facilitate timely access to genetic testing for men with mPC.
The OlympiA randomized phase III trial compared 1 year of olaparib (OL) or placebo (PL) as adjuvant therapy in patients with germline
, high-risk human epidermal growth factor receptor 2-negative ...early breast cancer after completing (neo)adjuvant chemotherapy (NACT), surgery, and radiotherapy. The patient-reported outcome primary hypothesis was that OL-treated patients may experience greater fatigue during treatment.
Data were collected before random assignment, and at 6, 12, 18, and 24 months. The primary end point was fatigue, measured with the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Secondary end points, assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 item, included nausea and vomiting (NV), diarrhea, and multiple functional domains. Scores were compared between treatment groups using mixed model for repeated measures. Two-sided
values <.05 were statistically significant for the primary end point. All secondary end points were descriptive.
One thousand five hundred and thirty-eight patients (NACT: 746, ACT: 792) contributed to the analysis. Fatigue severity was statistically significantly greater for OL versus PL, but not clinically meaningfully different by prespecified criteria (≥3 points) at 6 months (diff OL
PL: NACT: -1.3 95% CI, -2.4 to -0.2;
= .022; ACT: -1.3 95% CI, -2.3 to -0.2;
= .017) and 12 months (NACT: -1.6 95% CI, -2.8 to -0.3;
= .017; ACT: -1.3 95% CI, -2.4 to -0.2;
= .025). There were no significant differences in fatigue severity between treatment groups at 18 and 24 months. NV severity was worse in patients treated with OL compared with PL at 6 months (NACT: 6.0 95% CI, 4.1 to 8.0; ACT: 5.3 95% CI, 3.4 to 7.2) and 12 months (NACT: 6.4 95% CI, 4.4 to 8.3; ACT: 4.5 95% CI, 2.8 to 6.1). During treatment, there were some clinically meaningful differences between groups for other symptoms but not for function subscales or global health status.
Treatment-emergent symptoms from OL were limited, generally resolving after treatment ended. OL- and PL-treated patients had similar functional scores, slowly improving during the 24 months after (N)ACT and there was no clinically meaningful persistence of fatigue severity in OL-treated patients.
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